CN113018298B - Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof - Google Patents
Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof Download PDFInfo
- Publication number
- CN113018298B CN113018298B CN202110256949.8A CN202110256949A CN113018298B CN 113018298 B CN113018298 B CN 113018298B CN 202110256949 A CN202110256949 A CN 202110256949A CN 113018298 B CN113018298 B CN 113018298B
- Authority
- CN
- China
- Prior art keywords
- inhibitor
- compound
- pharmaceutical composition
- promyelocytic leukemia
- leukemia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 18
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 101000573199 Homo sapiens Protein PML Proteins 0.000 abstract description 3
- 102000054896 human PML Human genes 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 20
- 229940125904 compound 1 Drugs 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- -1 coated preparation Substances 0.000 description 8
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 231100000060 cardiovascular toxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- YMNCVRSYJBNGLD-KURKYZTESA-N cephalotaxine Chemical compound C([C@@]12C=C([C@H]([C@H]2C2=C3)O)OC)CCN1CCC2=CC1=C3OCO1 YMNCVRSYJBNGLD-KURKYZTESA-N 0.000 description 1
- DSRNKUZOWRFQFO-UHFFFAOYSA-N cephalotaxine Natural products COC1=CC23CCCN2CCc4cc5OCOc5cc4C3=C1O DSRNKUZOWRFQFO-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 231100000828 respiratory toxicity Toxicity 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 231100000342 urinary toxicity Toxicity 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an inhibitor for treating promyelocytic leukemia and a pharmaceutical composition thereof, wherein the inhibitor has the following structure:
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an inhibitor for treating promyelocytic leukemia and a pharmaceutical composition thereof.
Background
Acute Promyelocytic Leukemia (APL) is a malignant disease of hematopoietic tissues, mainly manifested by malignant proliferation of granulocytic progenitor cells, characterized by an unlimited proliferation of a large number of leukemia cells in bone marrow and other hematopoietic tissues and entry into the peripheral blood. Patients with the disease often get sick suddenly and quickly, and if the patients are not treated, the course of the disease usually does not exceed 6 months. Infections and bleeding are common in the clinic and are often fatal as a result. The etiology is still not completely understood, and many factors are related to the pathogenesis of leukocytes, such as viral infection, radionuclide irradiation, chemical factors, drugs, and genetic factors. The common diseases of children and adults under 35 years old have complicated etiology and pathogenesis of leukemia, and chemotherapy drugs are difficult to completely eliminate leukemia cells in vivo, so the prognosis is very poor.
At present, the main treatment methods are as follows: chemotherapy, induced differentiation therapy, arsenical therapy, hematopoietic stem cell transplantation and new therapeutic modalities (liposomal retinoic acid, histone deacetylase inhibitors, monoclonal antibodies and the like). The common medicines for chemotherapy comprise adrenocortical hormone, methotrexate, 6-mercaptopurine, aleucocytic anhydride, cyclophosphamide, vincristine, daunorubicin, cephalotaxine and the like, and the toxic and side effects are strong, so that patients are often accompanied by alopecia, nausea, vomiting, inappetence, abdominal pain, diarrhea, oral mucosa ulcer, sphagitis and the like, and other hepatotoxicity, cardiovascular toxicity, respiratory toxicity, urinary toxicity and the like. Tretinoin (ATRA) is commonly used for induced differentiation therapy, and in-vitro experiments prove that the ATRA can induce the differentiation of leukemia cell strains (such as HL-60 cells) and acute promyelocytic leukemia cells, is mainly used for the remission therapy of early relapse, can obviously improve the prognosis of patients, but the mechanism of inducing differentiation therapy for APL is not clarified, and most cases are easy to generate drug resistance relapse. Arsenic therapy is commonly used for refractory or relapsed APL that is ineffective in ATRA or combination chemotherapy, and other applicable cases, with strong toxic side effects. Hematopoietic stem cell transplantation is an important treatment option for patients with secondary or multiple remissions, and although 15-20% of transplant-related mortality exists, the survival rate of patients can be effectively improved, and if appropriate donors exist, HSCT treatment should be selected. Therefore, the discovery of efficient novel therapeutic drugs enriches the selection of combination therapy and has great practical significance in relieving APL patients.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide an inhibitor for treating promyelocytic leukemia and a pharmaceutical composition thereof, wherein the inhibitor has good inhibitory activity on human promyelocytic leukemia cells HL-60, can be used for developing a new inhibitor for treating promyelocytic leukemia, provides a new choice for the field of leukemia treatment, and has good application value.
The technical scheme of the invention is realized as follows:
an inhibitor for use in the treatment of promyelocytic leukemia, the inhibitor having a compound of the structure:
further, the pharmaceutically acceptable salt of the compound is hydrochloride, hydrobromide, nitrate, methanesulfonate, sulfate, phosphate, succinate, malate, fumarate, maleate, p-toluenesulfonate, tartrate, citrate, formate, acetate, oxalate, trifluoroacetate, trifluoromethanesulfonate.
A pharmaceutical composition comprising a compound as described above or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound as described above, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Furthermore, the mass ratio of the compounds in the pharmaceutical composition is 0.1-99%.
Furthermore, the mass ratio of the compound in the medicine composition is 0.5-95%.
The administration amount of the inhibitor provided by the present invention may vary depending on the route of administration, age, weight of the patient, type and severity of the disease to be treated, etc., and the daily dose thereof may be 0.01 to 10mg/kg of body weight, preferably 0.1 to 5mg/kg of body weight. One or more administrations may be carried out.
It can be administered orally in the form of solid or liquid, such as powder, tablet, coated preparation, capsule, solution, syrup, or dripping pill.
The injection can be solid or liquid preparation, such as powder injection, solution injection, etc.
Compared with the prior art, the invention has the following beneficial effects:
the inhibitor (2- (4, 5-dimethyl-1- (pyridine-3-yl) -1H-pyrrole-3-yl) 2-ethyl phenylacetate) provided by the invention has good inhibitory activity on human promyelocytic leukemia cells HL-60, can be used for developing a new inhibitor for treating promyelocytic leukemia, provides a new choice for the field of leukemia treatment, and has good application value.
Drawings
FIG. 1-IC 50 inhibition curves of Compound 1 against leukemia cell line HL-60.
Detailed Description
The invention is described in further detail below with reference to the drawings and the detailed description.
The structure of the compound provided by the invention is as follows:
the chemical name is: ethyl 2- (4, 5-dimethyl-1- (pyridin-3-yl) -1H-pyrrol-3-yl) 2-phenylacetate (hereinafter: Compound 1), the half growth inhibitory concentration IC50 of a leukemia tumor cell line was measured:
first, experiment principle
MTS is MTT analogue, succinate dehydrogenase in mitochondria of living cells can metabolize and reduce MTS to generate soluble Formazan (Formazan) compound, and the soluble Formazan compound can be directly dissolved in a culture medium. When in detection, only a small amount of CellTiter is needed
The Aqueous One Solution reagent is directly added into the culture medium in the culture plate hole, incubated for 1-4h, and then the absorbance value of 490nm is read by a microplate reader. The optical density OD (490nm) value of Compound 1 is proportional to the number of living cells. Cisplatin and paclitaxel were used as positive controls for the assay. IC50 values for Compound 1 were determined by concentration effect growth curve calculations.
Second, experimental instrument
CO2Incubator (Thermo), clean bench (Thermo), multifunctional enzyme label (MULTISKAN FC)
Third, the experimental procedure
1. Inoculating cells: preparing single cell suspension by using culture solution (RMPI1640) containing 10% fetal calf serum, inoculating 5000-15000 cells per well into a 96-well plate, wherein the volume of each well is 100 mu l, and the cells are inoculated and cultured 12-24 hours in advance.
2. Adding a solution of the test compound: compound 1 was dissolved in DMSO, and Compound 1 was rescreened at a concentration of 40. mu.M, 8. mu.M, 1.6. mu.M, 0.32. mu.M, 0.064. mu.M, with a final well volume of 200. mu.l, 3 wells for each treatment.
3. Color development: after culturing for 48 hours at 37 ℃, removing culture solution in the hole of the adherent cells, and adding 20 mul of MTS solution and 100 mul of culture solution into each hole; suspension cell HL-60 abandons 100. mu.l of culture supernatant, and 20. mu.l of MTS solution is added into each well; setting 3 blank multiple wells (mixed solution of 20 mul MTS solution and 100 mul culture solution), continuing incubation for 2-4 hours, and measuring the light absorption value after the reaction is fully performed.
4. Color comparison: selecting 492nm wavelength, reading the light absorption value of each hole by a multifunctional microplate reader (MULTISKAN FC), recording the result, drawing a cell growth curve by taking the concentration as an abscissa and the cell survival rate as an ordinate after data processing, and calculating the IC50 value of the compound.
5. Positive control compound: for each experiment, two positive compounds of cisplatin (DDP) and paclitaxel (Taxol) are set, a cell growth curve is drawn by taking the concentration as an abscissa and the cell survival rate as an ordinate, and an IC50 value of the compound is calculated.
Fourth, experimental results
1) Inhibition rate: inhibition rate of (1-A)Sample (I)/APositive control)*100％
The IC50 inhibition curve of Compound 1 against leukemia cell line HL-60 is shown in FIG. 1, and the growth inhibition rate of Compound 1 and the control compounds cisplatin and paclitaxel against IC50(μ M) of leukemia cell line HL-60 is shown in the following table.
| Compound (I) | Leukemia HL-60 |
| |
16.91±0.29 |
| Cisplatin (Positive control) | 4.956±0.283 |
| Paclitaxel (Positive control) | <0.008 |
Simultaneously, adding 4% sulfuric acid ethanol solution into Compound 1, adjusting pH value to 4, filtering, and drying to obtain corresponding sulfate Compound; adding 4% hydrochloric acid solution into Compound 1, adjusting pH to 4, filtering, and drying to obtain corresponding hydrochloride Compound; adding 4% tartaric acid solution into Compound 1, adjusting pH to 4, filtering, and drying to obtain tartrate Compound; the corresponding citrate Compound can be prepared by adding 4% citric acid solution to Compound 1, adjusting the pH to 4, filtering, and drying.
Finally, it should be noted that the above-mentioned examples of the present invention are only examples for illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. Not all embodiments are exhaustive. All obvious changes and modifications of the present invention are within the scope of the present invention.
Claims (6)
1. An inhibitor for use in the treatment of promyelocytic leukemia, wherein the inhibitor is a compound having the structure:
2. the inhibitor for treating promyelocytic leukemia according to claim 1, wherein the pharmaceutically acceptable salt of the compound is hydrochloride, hydrobromide, nitrate, methanesulfonate, sulfate, phosphate, succinate, malate, fumarate, maleate, p-toluenesulfonate, tartrate, citrate, formate, acetate, oxalate, trifluoroacetate, trifluoromethanesulfonate.
3. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition according to claim 4, wherein the mass ratio of the compounds in the pharmaceutical composition is 0.1-99%.
6. The pharmaceutical composition according to claim 5, wherein the mass ratio of the compounds in the pharmaceutical composition is 0.5-95%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110256949.8A CN113018298B (en) | 2021-03-09 | 2021-03-09 | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110256949.8A CN113018298B (en) | 2021-03-09 | 2021-03-09 | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113018298A CN113018298A (en) | 2021-06-25 |
| CN113018298B true CN113018298B (en) | 2022-05-03 |
Family
ID=76467442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110256949.8A Active CN113018298B (en) | 2021-03-09 | 2021-03-09 | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113018298B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015018182A1 (en) * | 2013-08-05 | 2015-02-12 | 北京京朋汇药业研究发展有限公司 | Phenylacetic acid derivative and antitumor use thereof |
| CN107362166A (en) * | 2017-08-01 | 2017-11-21 | 中国科学院昆明植物研究所 | Tetrahydropyridine simultaneously application of (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 in pharmacy |
-
2021
- 2021-03-09 CN CN202110256949.8A patent/CN113018298B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015018182A1 (en) * | 2013-08-05 | 2015-02-12 | 北京京朋汇药业研究发展有限公司 | Phenylacetic acid derivative and antitumor use thereof |
| CN107362166A (en) * | 2017-08-01 | 2017-11-21 | 中国科学院昆明植物研究所 | Tetrahydropyridine simultaneously application of (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 in pharmacy |
Non-Patent Citations (1)
| Title |
|---|
| Anticancer Activity of Phenolic Acids of Natural or Synthetic Origin: A Structure-Activity Study;Catarina A. Gomes等;《Journal of Medicinal Chemistry》;20031111;第46卷(第25期);第5395-5401页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113018298A (en) | 2021-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108159038A (en) | A kind of pharmaceutical composition and its purposes in the drug for preparing treatment multi-drug resistance of the tumor | |
| UA125892C2 (en) | An aurora a kinase inhibitor for use in the treatment of neuroblastoma | |
| CN109464460A (en) | A kind of pharmaceutical composition and its application in preparation of anti-tumor drugs improving anti-tumor drug sensibility | |
| JPS58208222A (en) | Enhancing agent for effect of antitumor agent | |
| CN107362166B (en) | Application of tetrahydropyrido [4,5- ] thieno [2,3- ] pyrimidine-4 (3) -ketone compound in pharmacy | |
| CN114796228A (en) | Application of pyrido [1,2-a ] pyrimidone compound | |
| CN113018298B (en) | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof | |
| CN113925867A (en) | Application of dronedarone hydrochloride and 5-fluorouracil in preparation of antitumor drugs | |
| AU2020248270B2 (en) | Chiauranib for treatment of small cell lung cancer | |
| US12048711B2 (en) | Composition and use thereof in the manufacture of medicament for treating cancer | |
| CN113274394A (en) | Pharmaceutical composition for treating tyrosine kinase inhibitor drug-resistant non-small cell lung cancer | |
| US20220313652A1 (en) | Use of compound or pharmaceutically acceptable salt, dimer or trimer thereof in manufacture of medicament for treating cancer | |
| CN114569728B (en) | Composition, application and medicine thereof | |
| CN114748479A (en) | Pharmaceutical composition for preventing and/or treating cancer | |
| CN1301111C (en) | Use of phenoxthine compounds in preparing medicnies for inhibiting cancers and promoting radio-sensitive medicines | |
| CN115721722B (en) | Pharmaceutical composition for treating EGFR-TKI resistant non-small cell lung cancer | |
| CN112336864A (en) | Application of proflavine in lung cancer treatment | |
| CN105434432B (en) | N-Hydroxyphthalimide class compound application in preparation of anti-tumor drugs | |
| WO2022198777A1 (en) | Application of triazole compound in preparation of antitumor drugs | |
| WO2022199656A1 (en) | Pharmaceutical combination, kit containing same, and use thereof | |
| EP0476391A2 (en) | Anti-AIDS virus composition containing cepharanthine as active compound | |
| CN104825455B (en) | The purposes of Buddhist nun is replaced according to Shandong | |
| CN114014853B (en) | Curcumin berberine eutectic crystal and pharmaceutical composition thereof | |
| RU2195937C1 (en) | Combined antituberculosis preparation (rizobutol) | |
| CN113461708A (en) | Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |